BACKGROUND AND AIMS: Interferon regulator factor 3 (IRF3) executes multiple transcriptional and non-transcriptional functions that regulate the development of metabolic liver diseases. However, the contribution of the tr...BACKGROUND AND AIMS: Interferon regulator factor 3 (IRF3) executes multiple transcriptional and non-transcriptional functions that regulate the development of metabolic liver diseases. However, the contribution of the transcriptional and non-transcriptional activities of IRF3 to hepatic fibrosis is unknown. APPROACH AND RESULTS: Chronic carbon tetrachloride (CCl 4 ) and choline-deficient L-amino acid-defined-diets both induced fibrosis in C57BL/6J (wild-type) and mice expressing only non-transcriptional IRF3 activity ( Irf3S1/S1 ) but not Irf3 -deficient ( Irf3-/- ) mice. HSC-specific deletion of Irf3 ( Lrat-Irf3 ) also attenuated CCl 4 -induced fibrosis. Molecular pathways associated with the regulation of extracellular matrix were upregulated during differentiation in primary HSCs from wild-type and Irf3S1/S1 , but not Irf3-/- , mice. Fibrogenic gene expression was also reduced in primary HSCs from Irf3-/- , but not Irf3S1/S1 , mice upon TGFβ stimulation. IRF3 gene silencing in LX2 cells suppressed TGFβ-induced fibrogenic gene expression and collagen production. Proteomic analysis identified stress granule (SG) associated proteins within the IRF3 interactome, and IRF3 localized to SGs in LX2 cells upon stimulation with poly(I:C) or TGFβ. Mechanistically, differentiation of primary HSCs or stimulation of LX2 cells with TGFβ induced accumulation of endogenous double-stranded RNA (dsRNA), which triggered assembly of IRF3-containing SGs in a TLR3-dependent mechanism. TGFβ stimulated SG assembly in primary HSCs from wild-type and Irf3S1/S1 , but not Irf3-/- , mice, and SGs were detected in fibrotic human livers. CONCLUSION: The non-transcriptional activity of IRF3 is a key driver of hepatic fibrogenesis. Non-transcriptional activity of IRF3 is activated by the accumulation of endogenous dsRNA and TLR3-dependent assembly of IRF3-containing SGs and acts as a central regulator of HSC activation and hepatic fibrogenesis.
Hernandez-Gea V, Paradis V, Guindi M
… +28 more, Alves VAF, Aqul A, Cerda E, Darwish Murad S, Das P, Di Giorgio A, de Freitas LAR, Grammatikopoulos T, Harada K, Hernandez N, Ibrahim SH, Kakar S, Karpen S, Kleiner DE, Ormeci N, Qi X, Sakhuja P, Schinoni MI, Saxena R, Sayadi A, Shukla A, Tiniakos DG, Verna E, Wong K, Elkrief L, Sempoux C, Heller T, Rautou PE
Noncirrhotic portal hypertension has historically been described using heterogeneous and region-specific terminology-such as idiopathic portal hypertension (IPH), noncirrhotic portal fibrosis (NCPF), obliterative portal...Noncirrhotic portal hypertension has historically been described using heterogeneous and region-specific terminology-such as idiopathic portal hypertension (IPH), noncirrhotic portal fibrosis (NCPF), obliterative portal venopathy, and nodular regenerative hyperplasia-leading to substantial variability in diagnosis, reporting, and international research collaboration. Differences in guideline definitions from major societies (AASLD, EASL, and APASL), together with the presence of characteristic histologic lesions in patients without clinically overt portal hypertension, have further complicated disease classification. To address these challenges, a large, multisociety, international initiative was convened to harmonize nomenclature and diagnostic criteria. Representatives from liver, pathology, and pediatric hepatology societies across the Americas, Europe, and Asia participated in a structured consensus process that included specialized working groups and external Delphi validation. The initiative produced a globally harmonized and implementable diagnostic framework. Consensus was reached that the terms porto-sinusoidal vascular disorder (PSVD) and NCPF may be used interchangeably when identical diagnostic criteria are applied, and that they should be written as PSVD or NCPF. The diagnosis was defined as fundamentally clinicopathological, requiring integrated assessment. Core principles include the need for a high-quality liver biopsy (≥10 mm), mandatory exclusion of cirrhosis, and systematic exclusion of specific alternative conditions. Importantly, the consensus recognizes that PSVD or NCPF may be diagnosed even without clinical portal hypertension and may coexist with other liver diseases, provided cirrhosis is excluded. Standardized major and minor histologic criteria were developed collaboratively by expert pathologists and externally validated. Features of portal hypertension were harmonized into specific and nonspecific categories applicable to routine clinical practice. An integrated diagnostic scoring system incorporating histology, clinical features, associated conditions, and concommitant etiologies was developed and validated using the Delphi method. This consensus provides the first internationally endorsed, unified framework for the diagnosis of PSVD or NCPF. Its global implementation is expected to reduce diagnostic variability, improve comparability across regions, and facilitate the development of robust, internationally harmonized clinical and translational research cohorts.
Valenzuela-Pérez L, Kim Lee HS, Bayer RL
… +20 more, Manna DF, Mishra SK, Washington AM, Hassan AA, Sidahmed MM, Ssali E, Dinc EJ, Manwana BK, Ibrahim A, Guo Q, Herman A, Graham RP, Pavelko KD, Gores GJ, Starlinger P, Revelo XS, Ibrahim SH, Kostallari E, Bamidele AO, Hirsova P
BACKGROUND AND AIMS: Unresolved inflammation and fibrosis are defining features of metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of steatotic liver disease that can advance to cirrhosis and...BACKGROUND AND AIMS: Unresolved inflammation and fibrosis are defining features of metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of steatotic liver disease that can advance to cirrhosis and hepatocellular carcinoma. While innate immune mechanisms in MASH have been extensively characterized, the role of CD4+ T cells remains poorly understood despite their central function in orchestrating immune responses through effector and regulatory mechanisms. APPROACH AND RESULTS: Integrated single-cell proteomic, transcriptomic, and functional analyses were used to investigate the CD4+ T-cell landscape in murine and human MASH. We delineated a profound shift in the differentiation of intrahepatic and peripheral CD4+ T cells toward Th1, regulatory, and cytotoxic phenotypes in murine and human MASH. Notably, hepatic CD4+ T cells exhibited heightened effector activity and elevated secretion of proinflammatory cytokines, thus amplifying inflammatory signaling cascades. The CD4+ T-cell reprogramming in MASH also included the induction of the co-stimulatory receptor OX40. In parallel, OX40 ligand (OX40L)-expressing monocyte-derived macrophages and dendritic cells accumulated in MASH livers, establishing a feed-forward CD4+ T cell-myeloid activation loop. Therapeutic blockade of the OX40-OX40L axis, in turn, reversed liver pathology in mice with established MASH and reduced disease markers in an ex vivo human liver model. Furthermore, genetic depletion or functional inhibition of CD4+ T cells attenuated fibrosis, accompanied by decreased infiltration of monocyte-derived macrophages. CONCLUSIONS: These studies provide a comprehensive single-cell proteogenomic atlas of CD4+ T cells in MASH and identify an OX40-dependent CD4+ T cell-macrophage axis as a promising therapeutic target for the treatment of MASH and liver fibrosis.
Gerussi A, Sebode M, Nofit E
… +11 more, Stoelinga A, Bernasconi D, Leburgue A, Invernizzi P, Schramm C, Van Hoek B, Tiniakos D, Terracciano L, Carbone M, Lohse AW, ERN RARE-LIVER, Global PBC Study Group and International Autoimmune Hepatitis Group (IAIHG)
BACKGROUND AND AIMS: Heterogeneity in the definition, diagnosis and treatment of primary biliary cholangitis-autoimmune hepatitis (PBC-AIH) is present in guidelines and daily practice. This initiative aimed to establish...BACKGROUND AND AIMS: Heterogeneity in the definition, diagnosis and treatment of primary biliary cholangitis-autoimmune hepatitis (PBC-AIH) is present in guidelines and daily practice. This initiative aimed to establish expert consensus on terminology, diagnosis and management. APPROACH AND RESULTS: The initiative was endorsed by the ERN RARE-LIVER, the Global PBC Study Group and the IAIHG, in partnership with the European Society of Pathology. Using a modified RAND/UCLA Appropriateness Method, the Delphi process involved two voting rounds. The final panel comprised 74 hepatologists and 14 liver pathologists from diverse geographic regions. Consensus was reached that PBC-AIH should be defined as a variant rather than an overlap syndrome. Additional agreement was achieved on diagnostic criteria and the prerequisite of liver biopsy to make the diagnosis. The panel agreed that the diagnosis should be periodically re-evaluated, since features can occur sequentially, and that PBC-AIH is associated with a worse prognosis than PBC alone unless treated by immunosuppression. The indication and choice of immunosuppressive therapy should be based on severity of interface hepatitis (ideally confirmed by review from an experienced hepatopathologist), disease stage, age, comorbidities, and patient preference. CONCLUSIONS: This Delphi initiative established consensus in a complex, understudied area lacking evidence-based guidelines. The resulting statements offer a basis for prospective studies and standardized clinical protocols, aiming to enhance consistent management of PBC-AIH.
Kamal H, Jargalsaikhan G, Enkhtaivan S
… +10 more, Lindahl K, Dashtseren B, Lkhagva-Ochir O, Ulziibadrakh T, Bungert A, Degasperi E, Lampertico P, Wedemeyer H, Dashdorj NB, Aleman S
BACKGROUND AND AIMS: Persistent HDV replication is associated with severe liver disease, yet predictors of spontaneous HDV RNA suppression remain poorly defined. We assessed the incidence and predictors of spontaneous HD...BACKGROUND AND AIMS: Persistent HDV replication is associated with severe liver disease, yet predictors of spontaneous HDV RNA suppression remain poorly defined. We assessed the incidence and predictors of spontaneous HDV suppression in a large cohort of chronic hepatitis D (CHD). METHODS: We included 1610 adult, treatment-naive CHD patients with ≥3 HDV RNA tests, who attended the Liver Center, Mongolia, between 2015 and 2025. Patients were categorized according to the last HDV RNA result: (1) Suppression (HDV RNA <50 IU/mL or HBsAg loss). (2) Persistent infection (HDV RNA ≥50 IU/mL). The incidence and predictors of HDV suppression during follow-up were analyzed using Kaplan-Meier curves and Cox regression. RESULTS: The median baseline age was 40.5 years, and 44.5% were male. Over a median of 3.9 years (IQR=2.1-5.9), 136 patients (8.4%) achieved spontaneous suppression, yielding cumulative incidences of 7.8% and 23.3% at 5 and 8 years, respectively. Independent predictors of HDV suppression were diabetes [adjusted hazard ratio (aHR) 2.13; 95% CI 1.21-3.74] and male sex (aHR 1.61; 95% CI 1.19-2.40), whereas higher baseline levels of HBsAg (aHR 0.42; 95% CI 0.31-0.55), HDV RNA (aHR 0.74; 95% CI 0.62-0.89), and ALT (aHR=0.35, 95% CI 0.21-0.57) were negatively associated. The risk of liver-related events was significantly lower in patients with HDV suppression than in those with persistent replication ( p =0.03). CONCLUSION: Diabetes, male sex, lower baseline HBsAg, HDV RNA, and ALT independently predicted HDV spontaneous suppression. These factors may inform treatment decisions in this era of emerging anti-HDV therapies.
Gupta P, Singh S, Gulati A
… +14 more, Mudgil P, Kalra N, Dutta N, Aggarwal Y, Bhujade H, Chaluvashetty S, Premkumar M, Taneja S, Verma N, De A, Sharma V, Sandhu MS, Singh V, Duseja A
BACKGROUND AND AIMS: To prospectively evaluate the diagnostic performance of a rapid abbreviated noncontrast MRI (AMRI) protocol compared to ultrasound (US) for HCC surveillance in a high-risk population with cirrhosis....BACKGROUND AND AIMS: To prospectively evaluate the diagnostic performance of a rapid abbreviated noncontrast MRI (AMRI) protocol compared to ultrasound (US) for HCC surveillance in a high-risk population with cirrhosis. APPROACH AND RESULTS: This prospective, single-center, diagnostic accuracy study (ClinicalTrials.gov: NCT05716620) enrolled patients with cirrhosis and annual HCC risk >5%. Participants underwent paired screening with US and noncontrast AMRI across 2 rounds, 6 months apart. Patients with positive findings on either imaging modality or clinical suspicion of HCC underwent multiphasic contrast-enhanced MRI (CE-MRI) as the reference standard. The primary outcome was the HCC detection rate (per-patient sensitivity) comparing AMRI and US. In 614 paired screening examinations across 404 patients, 97 underwent CE-MRI (based on positive screening), identifying 39 HCCs in 37 patients. AMRI demonstrated significantly superior sensitivity (94.6% [95% CI: 83.3-98.9] vs. 51.4% [95% CI: 34.7-67.8]; p <0.001) and specificity (96.6% [95% CI: 88.9-99.5] vs. 69.5% [95% CI: 55.8-80.8]; p <0.001). AUROC was 0.956 [95% CI: 0.913-0.997] vs. 0.604 [95% CI: 0.469-0.738] ( p <0.001). In the per-lesion analysis, AMRI detected 37 of 39 lesions (94.9%) versus US 20 of 39 (51.3%). Of HCCs detected by AMRI, 97.3% were early-stage Barcelona Clinic Liver Cancer Staging System 0 or A]. Interobserver agreement was "almost perfect" for AMRI (κ=0.929) versus "moderate" for US (κ=0.631). CONCLUSIONS: A rapid, noncontrast AMRI protocol shows superior per-patient sensitivity compared to US for HCC detection in patients with cirrhosis under surveillance. While these diagnostic findings are encouraging, prospective trials evaluating patient-level outcomes are essential before definitive guideline recommendations can be made.
BACKGROUND AND AIMS: Liver fibrosis is the principal histological determinant of mortality in metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms driving progression from steatosis to fibrosis rem...BACKGROUND AND AIMS: Liver fibrosis is the principal histological determinant of mortality in metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms driving progression from steatosis to fibrosis remain incompletely defined and effective antifibrotic therapies are limited. Although hepatocyte-derived exosomes under lipotoxic stress promote HSC activation, the pathogenic protein cargos remain undefined. This study sought to identify lipotoxicity-induced hepatocyte-derived exosomal proteins that drive MASH fibrogenesis and to define their mechanistic and therapeutic relevance. APPROACH AND RESULTS: Proteomic analysis of hepatocyte-derived exosomes from murine MASH livers and lipotoxic hepatocyte cultures identified N-acetyltransferase 10 (NAT10) as a stress-enriched exosomal cargo. zinc finger DHHC-type palmitoyltransferase 23 (ZDHHC23)-mediated palmitoylation promoted NAT10 nuclear export and exosomal loading. Functional studies demonstrated that exosomal NAT10 drove fibrogenic signaling in HSCs by enhancing N4-acetylcytidine (ac4C) RNA acetylation and stabilizing Ddr2 mRNA. Hepatocyte-specific Nat10 deletion or administration of NAT10-deficient exosomes attenuated liver fibrosis, whereas hepatocyte Nat10 overexpression exacerbated fibrogenesis in an exosome-dependent manner. In human liver samples, increased NAT10 expression and elevated extranuclear-to-nuclear ratio correlated with fibrosis severity. Finally, hepatocyte-targeted N-acetylgalactosamine-si Nat10 significantly ameliorated fibrosis in murine MASH models. CONCLUSIONS: This study links aberrant nuclear protein localization to subsequent exosome-mediated fibrogenic signaling in MASH and demonstrates that targeting this pathway, either by disrupting palmitoylation-dependent mislocalization or by hepatocyte-specific Nat10 inhibition, ameliorates liver fibrosis with concurrent metabolic benefit.
Aoe K, Tada T, Hiraoka A
… +56 more, Matono T, Hirooka M, Kariyama K, Tani J, Atsukawa M, Takaguchi K, Itobayashi E, Nishimura T, Tsuji K, Ishikawa T, Tajiri K, Tanaka H, Toyoda H, Ogawa C, Hatanaka T, Kakizaki S, Kawata K, Atsushi N, Kosaka H, Kuroda H, Yata Y, Nishikawa H, Imai M, Aoki T, Ochi H, Tamai H, Komatsu S, Matsuura T, Ueda Y, Kim SK, Ohama H, Tada F, Nakamura S, Nakamura Y, Yoshida O, Nouso K, Morishita A, Itokawa N, Okubo T, Arai T, Tsutsui A, Nagano T, Fukunishi S, Tanaka K, Koshiyama Y, Kanayama Y, Noritake H, Enomoto H, Matsui K, Kaibori M, Okamura J, Fukumoto T, Hiasa Y, Kudo M, Kumada T, RELPEC Group and HCC 48 Group
BACKGROUND AND AIMS: Atezolizumab plus bevacizumab is administered for unresectable HCC, with bevacizumab dosed by body weight, which may not adequately reflect body composition. This study evaluated the association betw...BACKGROUND AND AIMS: Atezolizumab plus bevacizumab is administered for unresectable HCC, with bevacizumab dosed by body weight, which may not adequately reflect body composition. This study evaluated the association between body surface area (BSA)-adjusted bevacizumab dosing, expressed as the bevacizumab-BSA index (BBI), and outcomes. APPROACH AND RESULTS: This retrospective study included 1507 patients with unresectable HCC treated with atezolizumab plus bevacizumab at 30 Japanese institutions. BBI was the ratio of actual to standard dose per BSA. Restricted cubic spline analyses identified the optimal BBI range. Outcomes were compared among BBI groups. Spline analysis revealed a nonlinear association between BBI and overall survival (OS), with an optimal BBI range of 106%-121%. Accordingly, the patients were classified into under (n=924), target (n=522), and over (n=61) groups. The median progression-free survival was significantly longer in the target group than in the nontarget group (10.3 vs. 6.5 mo, p <0.001), and the median OS was prolonged (24.9 vs. 19.2 mo, p =0.008). Multivariable analysis demonstrated that the target BBI group was independently associated with improved progression-free survival (HR, 0.807; 95% CI: 0.715-0.910; p <0.001) and OS (HR, 0.850; 95% CI: 0.733-0.985; p =0.031). The objective response rate was significantly higher in the Target group ( p =0.023), while treatment-related adverse event rates were comparable across the BBI groups, with no significant differences in proteinuria, hypertension, or other toxicities. CONCLUSIONS: BSA-adjusted bevacizumab dosing was associated with improved efficacy without increased toxicity in patients with unresectable HCC treated with atezolizumab plus bevacizumab.
BACKGROUND AND AIMS: Although the role of cardiometabolic risk factors (CMRFs) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed...BACKGROUND AND AIMS: Although the role of cardiometabolic risk factors (CMRFs) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRFs on mortality. APPROACH AND RESULTS: Multinational prospective cohort study (2015-2024) including hospitalized patients with AH across 32 centers in 14 countries. Diagnosis of AH was made using the National Institute on Alcohol Abuse and Alcoholism criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and acute-on-chronic liver failure grade, with liver transplantation as a competing risk. Nine hundred thirty-six participants were included; the mean age was 48±11.2 years, and 88.9% were male. At least 1 CMRF was present in 46.6%; median body mass index was 24.2 kg/m 2 [IQR: 22.8-28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 (19.3-31.4), 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (subdistribution hazard ratio [sHR] 1.03; 95% CI: 1.01-1.04), greater alcohol intake (per g/day; sHR: 1.001; 95% CI: 1.000-1.002), MELD (sHR: 1.04; 95% CI: 1.01-1.06), and acute-on-chronic liver failure grade 2-3 (sHR: 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified nonlinear body mass index analysis showed modestly lower mortality between 25 and 40 kg/m², with a higher risk above 40 kg/m². CONCLUSIONS: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher body mass index was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.
BACKGROUND AND AIMS: Steatotic liver disease (SLD) and liver fibrosis are major comorbidities in people with HIV (PWH). Guidelines recommend stepwise screening using the Fibrosis-4 (FIB-4) index followed by transient ela...BACKGROUND AND AIMS: Steatotic liver disease (SLD) and liver fibrosis are major comorbidities in people with HIV (PWH). Guidelines recommend stepwise screening using the Fibrosis-4 (FIB-4) index followed by transient elastography (TE), yet its accuracy and the extent of FIB-4 misclassification in PWH remain uncertain. We evaluated the diagnostic performance of FIB-4 against TE, quantified missed fibrosis, and assessed whether metabolic and HIV-specific factors improve risk prediction. APPROACH AND RESULTS: We conducted a multinational study of 4917 PWH without viral hepatitis coinfection or hazardous alcohol intake undergoing TE screening across 7 centers. SLD was defined by a controlled attenuation parameter ≥275 dB/m and classified as metabolic dysfunction-associated SLD (MASLD) or metabolic dysfunction-associated alcohol-related liver disease (MetALD). Significant fibrosis [liver stiffness measurement (LSM) ≥8 kPa] was present in 12.6% of participants, advanced fibrosis (LSM ≥11 kPa) in 6.1%, and SLD in 21.7% (20.6% MASLD, 1.1% MetALD). FIB-4 showed modest accuracy for significant fibrosis (AUROC 0.69, 95% CI 0.67-0.72) and misclassified 36% of fibrosis cases as low risk (FIB-4 <1.3). Performance was poorer in MASLD than in non-MASLD (AUROC 0.60 vs. 0.76; p <0.001). Participants with false-negative FIB-4 exhibited a more metabolic phenotype, including higher BMI and steatosis. Incorporating metabolic and HIV-specific factors improved discrimination and reclassification and enabled the development of the FIB-HIV score, which outperformed FIB-4 (AUROC 0.78 vs. 0.69; p <0.001). CONCLUSIONS: In PWH, liver fibrosis is common and frequently missed by FIB-4, particularly in MASLD. TE-centered screening strategies augmented by metabolic and HIV-specific indicators may improve early fibrosis detection and risk stratification.
BACKGROUND AND AIMS: Virologic profiling is mandatory for the clinical management of hepatitis B surface antigen (HBsAg) carriers, positive for antibody against hepatitis delta virus (anti-HDV). We analyzed the correlati...BACKGROUND AND AIMS: Virologic profiling is mandatory for the clinical management of hepatitis B surface antigen (HBsAg) carriers, positive for antibody against hepatitis delta virus (anti-HDV). We analyzed the correlations between serum HDV RNA, anti-HDV, HBV markers, and liver disease in a single-center cohort study. APPROACH AND RESULTS: Virologic, biochemical, imaging/histologic characteristics were studied in 146 consecutive HBsAg/anti-HDV carriers at baseline; in 31 interferon-treated patients, HDV/HBV markers were measured at the end of therapy (EOT), 24 weeks after EOT, and at the end of follow-up (EOF). HDV RNA was quantified with the Altostar-Quantification-Kit (Altona Diagnostics) and anti-HDV by 10-fold endpoint dilutions (Liaison XL Murex anti-HDV, DiaSorin). Liver disease was absent in 9/10 (90%) HDV RNA negative/anti-HDV-positive (all ≤1:100) and 2/136 (1.5%) viremic individuals (HDV RNA<500 IU/mL and anti-HDV≤1:100). The remaining 134 had liver disease (CHD), 110 (82.0%) cirrhosis; all but one had anti-HDV≥1:1000; HDV RNA levels were higher in cirrhotics [5.86 (4.93-6.43) vs. 5.01 (3.58-5.79) Log IU/mL, p =0.004], viremia peaking in early [6.02 (5.21-6.56) Log IU/mL] versus advanced cirrhosis [5.44 (4.71-6.06) Log IU/mL, p =0.006]. HDV RNA correlated with anti-HDV, HBsAg, HBcrAg, and ALT ( p <0.001). At multivariate HDV RNA independently associated with liver disease stage (β=0.244, p =0.003), ALT (β=0.220, p =0.001), and HBsAg levels (β=0.515, p <0.001). All but one of the 16 IFN responders had anti-HDV≤1:100 at EOF; all relapsers/non-responders had anti-HDV≥1:1000. CONCLUSIONS: Combined HDV RNA and anti-HDV quantification provides complementary information for characterizing HBV/HDV infection and monitoring treatment response. Declining anti-HDV levels are associated with virological control. These results prompt prospective multicentre studies of their role in the clinical and therapeutic management of patients with HBV/HDV coinfection.
BACKGROUND AIMS: Patients with acutely decompensated cirrhosis (ADC) present severe immune dysfunction characterized by smoldering systemic inflammation and persistent immunosuppression rendering them at increased risk o...BACKGROUND AIMS: Patients with acutely decompensated cirrhosis (ADC) present severe immune dysfunction characterized by smoldering systemic inflammation and persistent immunosuppression rendering them at increased risk of bacterial infections and acute-on-chronic liver failure (ACLF). APPROACH RESULTS: We explored the profile of 98 immunomodulatory lipid mediators in ADC patients with and without ACLF and their effects on leukocyte function. We performed LC-MS/MS-based lipidomics of 308 plasma samples longitudinally collected from 93 ADC patients with and without ACLF and integrated expression and flow cytometry data with functional assays in leukocytes. Lipidomics identified the linoleic acid-derived leukotoxin 9,10-dihydroxy-12-octadecenoic acid (9,10-DiHOME) as the only lipid mediator elevated in ACLF. 9,10-DiHOME levels followed the disease severity course and peaked when patients acquired infections and developed ACLF. Leukocytes from ADC patients showed increased expression of soluble epoxide hydrolase (sEH), the enzyme responsible for 9,10-DiHOME biosynthesis. In polymorphonuclear leukocytes, 9,10-DiHOME impaired degranulation, phagocytosis, and respiratory burst capacities. In mononuclear leukocytes, this lipid mediator induced the expression of the immunosuppressive marker MerTK, impaired their ability to produce cytokines in response to LPS and disrupted mitochondrial dynamics and autophagic responses. Inhibition of sEH in vivo reduced immunosuppressive responses in peritoneal macrophages and significantly attenuated MerTK expression in liver macrophages. CONCLUSIONS: These findings indicate that increased levels of the leukotoxin 9,10-DiHOME weakens immune-cell defensive responses and position sEH as a potential drug target in ADC.
BACKGROUND AND AIMS: Alpha-1 antitrypsin (AAT), encoded by the SERPINA1 gene, is primarily synthesized in the liver and secreted into the blood. The SERPINA1 Z allele encodes Z-AAT (Glu342Lys), a variant that self-associ...BACKGROUND AND AIMS: Alpha-1 antitrypsin (AAT), encoded by the SERPINA1 gene, is primarily synthesized in the liver and secreted into the blood. The SERPINA1 Z allele encodes Z-AAT (Glu342Lys), a variant that self-associates into polymers that are retained in hepatocytes and trigger inflammation and hepatic injury. Targeting and preventing Z-AAT polymerization allows a therapy to directly address the pathophysiology of AAT deficiency (AATD) associated liver disease. APPROACH AND RESULTS: A structure-based design approach was used to develop BMN 349, a small-molecule polymerization blocker capable of stabilizing Z-AAT to prevent new polymerization and promote hepatic clearance. BMN 349 bound Z-AAT ~150 times faster in vitro than wild-type M-AAT and promoted secretion and reduced polymer levels in a cell model of Z-AAT deficiency. Crystallography with M-AAT showed that BMN 349 partially displaces a region involved in polymerization, the reactive center loop proximal hinge. Oral dosing in female PiZ transgenic mice with 20-200 mg/kg/day BMN 349 for 30 days was associated with dose-dependent increases in total plasma Z-AAT and a concurrent decrease in circulating and liver Z-AAT polymers relative to vehicle-treated controls. Histopathologic and proteomic assessments of liver and plasma samples from these mice showed that doses ≥100 mg/kg/day of BMN 349 reduced liver inflammation and improved liver health biomarkers after 30 days. CONCLUSIONS: This study is the first to demonstrate a reduction in Z-AAT polymer burden without altering protein expression. Improvements in liver inflammation and function following BMN 349 treatment support further investigations of its therapeutic benefits for AATD liver disease.
Chalasani N, Vuppalanchi R, Noureddin M
… +10 more, Shiffman ML, Lawitz E, Mena E, Gunn NT, Ladron de Guevara L, Elgouhari H, Safadi R, Jamil K, Harrison SA, Alkhouri N
BACKGROUND AND AIMS: Belapectin reduced variceal development in a subgroup of patients with MASH cirrhosis. We report the efficacy and safety of belapectin in patients with MASH cirrhosis and portal hypertension without...BACKGROUND AND AIMS: Belapectin reduced variceal development in a subgroup of patients with MASH cirrhosis. We report the efficacy and safety of belapectin in patients with MASH cirrhosis and portal hypertension without varices at baseline. APPROACH AND RESULTS: NAVIGATE was a global phase 2b trial. Patients were randomized to intravenous (i.v.) belapectin 2 or 4 mg/kg lean body weight or placebo for 18 months, stratified by type 2 diabetes. The primary endpoint was the incidence of varices with esophagogastroduodenoscopy (EGD) or a composite endpoint (new varices, intercurrent events, or discontinuation) at 18 months with belapectin versus placebo in the full analysis set (FAS). In a pre-specified analysis, new varices were evaluated in all patients who underwent EGD at baseline and 18 months. The per-protocol (PP) population was patients treated for 18 months with EGD at 18 months. Of 357 randomized patients, 291 completed treatment. Baseline characteristics were comparable across cohorts. In the FAS, 17.8% with placebo versus 10.1% with belapectin 2 mg/kg developed varices, a 43.2% reduction ( p =0.13). In the per-protocol population (PP), varices occurred in 22.3% with placebo versus 11.3% with belapectin 2 mg/kg, a 50% reduction (unadjusted p =0.04). Belapectin 4 mg/kg had no significant effect on variceal development. For the composite endpoint at 18 months, no significant difference was observed between belapectin 2 mg/kg ( p =0.14) or 4 mg/kg ( p =0.261) and placebo in the FAS. Belapectin was well-tolerated with no safety signals. CONCLUSION: Belapectin 2 mg/kg lowered the development of new varices in MASH cirrhosis and portal hypertension.
Boehmler DJ, Baron RJ, Brain JA
… +17 more, Islam A, Kim Y, Gurevich A, Perkons NR, Zavriyev AI, Amin R, Andrew-Udoh J, Tuzneen Supan E, El Ghazal R, Hunt SJ, McClung G, Tischfield D, Ackerman D, Weljie AM, Weinfurtner K, Skuli N, Gade TPF
BACKGROUND AND AIMS: Metabolic inhibitors have demonstrated limited efficacy for cancer therapy due to metabolic plasticity and systemic toxicity. Locoregional therapies (LRT), such as transarterial embolization (TAE) or...BACKGROUND AND AIMS: Metabolic inhibitors have demonstrated limited efficacy for cancer therapy due to metabolic plasticity and systemic toxicity. Locoregional therapies (LRT), such as transarterial embolization (TAE) or transarterial chemoembolization (TACE), generate ischemic stress that reprograms the tumor microenvironment (TME) toward glycolytic dependency, creating an opportunity to sensitize hepatocellular carcinoma (HCC) to metabolic inhibition. This study investigated whether pharmacologic inhibition of lactate dehydrogenase (LDH) with NCATS-SM1441 could exploit TAE-induced metabolic vulnerabilities to improve therapeutic efficacy in HCC. APPROACH AND RESULTS: Human HCC cell lines were exposed to replete or ischemic (TAE-like) conditions and treated with the LDH inhibitor NCATS-SM1441. Glucose/lactate flux, adenosine triphosphate (ATP) levels, and viability were assessed. In vivo, a diethylnitrosamine (DEN)-induced rat HCC model was treated with intra-arterial NCATS-SM1441, TAE, or their combination. Drug distribution, tumor metabolism, necrosis, and survival were analyzed using mass spectrometry imaging, histopathology, T2-weighted magnetic resonance imaging (MRI), and survival metrics. Ischemic conditions induced LDHA expression and glycolytic flux, enhancing susceptibility to LDH inhibition. The combination of intra-arterial NCATS-SM1441 before embolization increased intratumoral drug accumulation, reduced systemic exposure, and synergized with TAE to suppress lactate production, promote tumor necrosis, and significantly extend local progression-free survival. CONCLUSIONS: TAE conditions the TME to create a therapeutically targetable glycolytic dependency. Combining TAE with LDH inhibition overcomes key limitations of metabolic inhibitors as monotherapies, enhancing local control and survival with minimal systemic toxicity, supporting integration of metabolism-targeted agents with LRT for unresectable HCC.
BACKGROUND AND AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors individually benefit patients with metabolic dysfunction-associated steatotic liver disease (M...BACKGROUND AND AIMS: Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors individually benefit patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the effect of GLP-1 receptor agonist-SGLT-2 inhibitor combination on the risk of major adverse liver and cardiovascular outcomes compared with either agent alone among patients with MASLD and type 2 diabetes (T2D). APPROACH AND RESULTS: This is a target trial emulation study using data from U.S. MarketScan databases. Propensity score-matched cohorts were built to compare (1) 4606 patients who received GLP-1 receptor agonist-SGLT-2 inhibitor combination with 18,424 who received only GLP-1 receptor agonist, and (2) 5368 patients who received this combination with 21,472 who received only SGLT-2 inhibitors. Cox regression models were conducted in on-treatment designs. Compared with GLP-1 receptor agonists, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a 39% lower risk of major adverse liver outcomes [HR 0.61 (95% CI 0.49-0.77)] and a 35% lower risk of major adverse cardiovascular events [HR 0.65 (0.60-0.70)] during a median follow-up of 6.3 months. Compared with SGLT-2 inhibitors, the combination was associated with a 43% lower risk of major adverse liver outcomes [HR 0.57 (0.46-0.69)] and a 20% lower risk of major adverse cardiovascular events [HR 0.80 (0.75-0.86)] during a median follow-up of 6.0 months. CONCLUSIONS: In this study, the GLP-1 receptor agonist-SGLT-2 inhibitor combination was associated with a lower risk of major adverse liver and cardiovascular outcomes compared with either agent alone among patients with MASLD and T2D.